This invention relates to a method for producing a nicotine-containing composition having a controlled release rate of nicotine. More particularly, this invention relates to a process for producing product comprising nicotine and a cation exchange resin, such product having a nicotine release rate of at least 70% over a 10 minute period.
Nicotine is a well know, highly characterized alkaloid that can be isolated from the dried leaves of Nicotiana tabacum. Its numerous commercial uses include utilities such as a fumigant, an insecticide and the like. It is therapeutically valuable in the treatment of the smoking withdrawal syndrome. This treatment is based on the fact that the administration of nicotine into the body has been readily accomplished by the method of smoking, e.g., from cigarettes, pipes or cigars. The smoker experiences a satisfactory sensation from such administration. However, smoking may be associated with health hazards not necessarily associated with nicotine administration itself.
As a result, non-smoking methods have been devised to administer nicotine to the body. These include nicotine-containing chewing gums, nicotine-impregnated dermal patches, nicotine inhalers and the like. A variety of patents have disclosed such products.
In U.S. Pat. No. 4,692,462 discloses a transdermal drug delivery system having a drug reservoir composed, in part, of an ion exchange resin. The drug reservoir also contains water and a hydrophilic polymer gel. The presence of the water causes the drug to become unbound and therefore has a disadvantageously short shelf life.
WO 94/08572 is similar to the above-identified ""462 patent but has a nonaqueous component, which increases the shelf life.
U.S Pat. No. 3,901,248 discloses a chewable smoking substitute composition that comprises a chewing gum base and nicotine in combination with certain saliva-insoluble cation exchange resins. When such composition is chewed, nicotine is released in small and reduced amounts into the mouth, within the first few minutes of chewing. The composition is marginally effective in inducing the pleasurable sensation of smoking that is typically desired from those engaged in the therapy that incorporates such chewing gum.
The present invention relates to a nicotine product having a nicotine release rate of not less than 70% over a 10 minute period as well as a process to produce such product Such a product is produced by a process comprising the steps of:
(a) preparing an aqueous solution of an organic polyol;
(b) mixing said aqueous solution of the organic polyol with a cation exchange resin selected from the group consisting of (i)xe2x80x94a methacrylic, weakly acidic type of resin containing carboxylic functional groups (ii)xe2x80x94polystyrene, strongly acidic type of resin containing sulfonic functional groups and (iii)xe2x80x94polystyrene, intermediate acidic type of resin containing phosphonic functional groups thereby forming a cation exchange resin mixture having some of its ion exchange sites partially blocked with said polyol;
(c) admixing with said mixture of step (b) an aqueous solution of nicotine to form a nicotine-coated cation exchange resin admixture; and
(d) removing water from said admixture.
The nicotine composition having a nicotine release rate of not less than 70% over a ten minute period results.
In accordance with the present invention, a process, product from such process and composition resulting from this process are disclosed. The composition is one that contains nicotine. The nicotine in the composition herein, has a release rate of not less than 70% over a period of 10 minutes. The method by which such release rate is determined is described in more detail in the U.S.P. Official Monograph, Volume 25, pages 1225 and 1226, incorporated herein by reference.
The product produced by the process according to the present invention contains, in addition to the above-disclosed nicotine, a cation exchange resin and an organic polyol.
Any nonionic pharmaceutical grade cationic ion-exchange resin used to bind anionic molecules at the ion exchange sites may be employed in this invention. Examples of such cationic materials are: the those bearing a carboxylic acid group, such as a weakly acidic type of resin containing carboxylic functional groups (these resins are typically derived from polymers or copolymers of methacrylic acid or polymethacrylic acid); the strongly acidic type of resins containing sulfonic functional groups (these resins are typically derived from polymers of styrene or copolymers of styrene and divinylbenzene); or the intermediate acidic type of resins containing phosphonic acid functional groups (these resins are typically derived from polymers of styrene or copolymers of styrene and divinylbenzene).
Cationic ion exchange resins are well know in the art and the present invention encompasses all of these. Representative cation exchange resins of use in accordance with the present invention are disclosed in U.S. Pat. No. 3,901,258 incorporated herein by reference. The preferred cation exchange resins are those known in the art as the Amberlite(copyright) resins and include, for example, Amberlite(copyright) IR-20, Amberlite(copyright) IRP-69, Amberlite(copyright) IRP-64, Amberlite(copyright) IRP-58, Amberlite(copyright) IRC-50, Amberlite(copyright) IRP-69, etc.
The product in accordance with the present invention also contains as organic polyol. The organic polyol is a non-toxic C2 to C12 linear or branched hydrocarbon having at least 2 hydroxy groups or a non-toxic C5 to C12 cyclic or heterocyclic hydrocarbon having at least 2 hydroxy groups. The former compounds are illustrated by the polyhydric alcohols such as 1,3-dihydroxypropane, hexylene glycol, glycerin, sorbitol etc., the latter by inositol and the carbohydrates such as glucose, sucrose, etc.
In carrying the process in accordance with the present invention, it is necessary to combine the organic polyol with the cation exchange resin to form a mixture (slurry). Any form of mixing is acceptable. However, it is important that the ratio of cation exchange resin to organic polyol is from about 1:1 to about 5:1, i.e., from about 1 gram of resin per gram of polyol to about 1 gram of resin per 200 mg. of polyol. Preferably, the ratio of cation exchange resin to organic polyol is from about 2:1 (1 gram of resin per 500 mg of polyol) to about 4:1 (1 gram of resin per 250 mg. of polyol), most preferably about 2.5:1 (1 gram of resin per 400 mg. of polyol).
To the mixture (slurry) formed as disclosed above, is admixed an aqueous solution of nicotine. The concentration of nicotine in the aqueous solution of nicotine is from about 5% by weight to about 40% by weight, i.e., about 50 mg to about 400 mg of nicotine in each gram of solution. Preferably there is about 10% to about 30% by weight, i.e., about 100 mg to about 300 mg, of nicotine for each gram of solution. Most preferably, the amount of nicotine for each gram of solution is about 150 mg, i.e., about 15% by weight.
The ratio of cation exchange resin to nicotine is from about 2:1 to about 10:1, i.e., 1 gram of resin per 500 mg of nicotine to about 1 gram of resin per 100 mg of nicotine.. Preferably, the ratio of cation exchange resin to nicotine is from about 3:1 to about 6:1, i.e., 1 gram of resin per 333 mg of nicotine to about 1 gram of resin per 167 mg of nicotine. Most preferably, the rato of cation exchange resin to nicotine is about 4:1, i.e., 1 gram of resin per 250 mg of nicotine.
The admixture, which is a water slurry of the cation exchange resin incorporating nicotine and the organic polyol is then dried to remove the water. Such drying can be carried out by any conventional means, i.e., dried over a purge of nitrogen, dried under vacuum, etc.. However, it should be noted that drying the admixture at temperatures in excess of 75-80xc2x0 C. cause the disadvantageous loss of nicotine and should be avoided.
The dried admixture, which is an lightly colored, brown powder, is typically sieved to a substantially uniform particle size before being used.
The composition of the final powdered product, i.e., the polyol modified-nicotine containing cation exchange resin of the present invention comprises 10 to 499 mg of nicotine, 10 to 499 mg of polyol and 980 to 2 mg of resin. Preferably, the composition of the final product is 100 to 200 mg of nicotine, 200 to 300 mg of polyol 600 to 500 mg of ion exchange resin. In its most preferred composition it has the following concentration of components: 150 mg nicotine; 240 mg of polyol; and 610 mg of ion exchange resin.
The following Examples demonstrate the process pf the present invention and the compositions resulting from such process. These Examples should not be regarded as limiting the invention in any sense.